摘要
血脂异常(dyslipidemia)是人群中的常见病和多发病,与冠心病、高血压、2型糖尿病、脑卒中等疾病密切相关。近年来我国血脂异常的患病率已明显升高,有关其发病机制的研究越来越引起重视。目前认为血脂异常是一个多因素疾病,除了受饮食和环境等因素影响外,一些易感基因的单核苷酸多态性(single nucleotide polymerphisms, SNPs)也与其密切相关。研究血脂异常的遗传易感基因对于开展针对性的人群预防,进行个体化治疗,有效的延缓或防止其发生发展具有重要的意义。目前已知数种基因突变与血脂异常的发生具有相关性,包括低密度脂蛋白受体基因、多种载脂蛋白和血管紧张素转化酶,胆固醇7α-羟化酶,前蛋白转化酶枯草溶菌素、细胞视黄酸结合蛋白、细胞色素P450 3A4及2C9等。研究这些基因与血脂异常的关系均是从这些基因的基因多态性与血脂异常的关系着手。
人细胞色素酶P450 (Cytochrome P450, CYP450)是人类重要的肝脏药物代谢酶,涉及到许多内、外源性物质的代谢。CYP450蛋白由CYP基因超家族编码,这组酶系包括CYP1-4四个家族和A、B、C、D、E亚家族,同工酶达数十种。在这些家族中,CYP3A是最大的的一族,包含4个功能基因CYP3A4、CYP3A5、CYP3A7和CYP3A43,及2个假定基因(CYP3AP1和CYP3AP2)。CYP3A5是CYP3A亚家族中的一种,其蛋白主要分布于肝脏,在肾脏和肺等其他部位中也有表达,在一些个体中CYP3A5占肝脏CYP3A总量的50%。
CYP3A5蛋白由CY3A5基因编码,人CYP3A5基因位于7号染色体q21-q22.1上,全长31.0kb,有13个外显子。CYP3A5基因存在着多个SNPs位点,野生型定义为*1,突变型按发现的顺序命名。迄今已经发现了CYP3A5*2、*3、*4、*5、*6、*7、*8等近30种CYP3A5突变型。目前研究证实,位于CYP3A5基因第3号内含子的6986密码子是决定CYP3A5表达及其活性的最关键因素。不同人群中CYP3A5*3等位基因变异有不同的分布,在中国人群中,CYP3A5*3基因型为CYP3A5*1／*1型(AA、野生型)、CYP3A5*1／*3型(GA、杂合突变型)和CYP3A5*3/*3型(GG、纯合突变型)
CYP3A5基因多态性引起了个体中CYP3A5蛋白结构的变化,从而引起了蛋白活性的变化,已有的研究表明其突变型蛋白的活性低于野生型。蛋白活性的变化,造成了对外源性物质代谢和内源性物质催化能力的不同,携带有突变型基因的个体代谢外源性物质和催化内源性物质的能力较携带野生型基因个体低,进而对某些物质的代谢及疾病的发生、发展产生不同影响。
由于CYP3A5参与多种与血脂代谢相关的内源性物质的转化,其基因多态性也影响他汀类药物的降血脂效应,但其本身与血脂关系如何目前尚不清楚。而且已知结构及功能与CYP3A5具有84%相似的CYP3A4在胆固醇和羟基化胆固醇的生成及代谢上发挥重要作用,目前已经发现CYP3A4基因多态性与血脂水平相关,如CYP3A4*3与治疗前较低的LDL-C具有关联性。此外CYP3A5在17-β雌二醇和雌酮的羟化反应中也发挥作用,雌激素通过增加低密度脂蛋白受体(low density lipoprotein receptor, LDLR)的表达来降低低密度脂蛋白胆固醇(low density lipoprotein-cholesterol, LDL-C),推测CYP3A5基因多态性可能引起雌激素羟化反应的个体差异使体内雌激素水平不同,导致血脂异常发生的危险不同,目前也已发现与CYP3A5同样参与催化17-p雌二醇和雌酮羟化反应的CYP2C9与血脂异常具有相关性。基于以上观点,推测CYP3A5基因多态性与血脂水平也可能存在联系。
为此,本研究以SNP为遗传标记,采取病例-对照的研究策略,运用TaqmanMGB探针的实时荧光定量PCR (the real-time PCR)基因分型方法,通过基因关联分析,进行CYP3A5*3等位基因的遗传多态性与血脂异常的关联研究,旨在从遗传学角度探讨这种疾病的发病机制,为其个体化预防和治疗提供参考资料。
目的
1.探讨CYP3A5基因多态性和血脂异常的关系。
2.探讨CYP3A5基因多态性和血脂水平的关系。
对象及方法
对象
所有研究对象均从我院心内科住院患者及健康体检人群中选取。包括321例血脂异常患者和258例正常对照者。血脂异常组入选标准：即禁食12小时后测血清总胆固醇(total cholesterol, TC)≥5.72mmol/L,或低密度脂蛋白胆固醇(1owdensity lipoprotein-cholesterol, LDL-C)≥3.36mmol/L,或高密度脂蛋白胆固醇(highdensity lipoprotein-cholesterol, HDL-C)≤0.9 mmol/L,或血清甘油三酯(Triglyceride,TG)≥1.70mmol/L,血脂中TC.LDL-C、HDL-C、TG至少2项或2项以上指标异常才被入选,其中男性162例,女性159例,年龄53.54±12.06岁。正常对照组入选标准：血脂各项指标均在正常范围内,血、尿常规和血生化、凝血功能、胸部X光及心电图检查均正常,男性11l例,女性147例,年龄52.69±11.66岁。所有研究对象均为自然人群,汉族且无血缘关系,排除肝病、肾病、肿瘤、糖尿病等其它严重的全身性疾病,且近期无服用任何降脂药物,女性无使用钙剂及围绝经期激素替代治疗者。
方法
实验对象于清晨空腹12小时以上,取静脉血采用标准酶比色法测定TC、LDL-C、HDL-C和TG。另取5ml静脉血置于EDTA-K2抗凝管按人血液DNA提取试剂盒操作步骤提取白细胞基因组DNA,运用TaqmanMGB探针实时荧光定量PCR(the real-time PCR)基因分型法,对CYP3A5*3(6986A→G)位点进行PCR扩增及SNP分型。并将血脂异常组及对照组中的CYP3A5*3各基因型者间的血脂水平进行比较。采用两独立样本t检验比较血脂异常组和对照组实验对象的年龄、性别等其他一般临床资料的差异,采用四格表资料的χ2检验比较血脂异常组和对照组的CYP3A5*3基因型频率及等位基因频率,各基因型者间的血脂水平比较采用单向方差分析法。P<0.05为差异有统计学意义。
结果1.血脂异常组和对照组中均检出AA野生型(CYP3A5*1／*1).GA杂合突变型(CYP3A5*／*3)和GG纯合突变型(CYP3A5*3／*3)三种基因型。
2.血脂异常组AA.GA.GG基因型频率分别为9%、46.1%、44.9%；对照组则为9.7%、39.5%、50.8%。血脂异常组A及G等位基因频率分别为32.1%、67.9%；对照组则为29.5%、70.5%。基因型及等位基因频率分布在两组比较均无显著性差异(P=0.279,P=0.336)。
3.血脂异常组及对照组中,A等位基因(AA+GA型)携带者的HDL-C水平(1.30±0.33 mmol/L,1.53±0.41 mmol/L)显著高于GG纯合型(1.21±0.29 mmol/L, 1.42±0.36 mmol/L)(P=0.011,P=0.034).其余血脂水平无显著性差异。
结论
1.汉族人群中CYP3A5*3等位基因包括AA野生型(CYP3A5*1／*1)、GA杂合突变型(CYP3A5*1/*3)和GG纯合突变型(CYP3A5*3/*3)三种基因型。
2.血脂异常组及对照组中,CYP3A5*3基因型及等位基因频率分布比较均无显著性差异(P>0.05),提示血脂异常发生可能与CYP3A5*3基因多态性无关。
3.血脂异常组及对照组中,CYP3A5*3 A等位基因携带者(AA+GA型)HDL-C水平高于非A等位基因携带者(GG型)(P<0.05)。其余血脂水平无显著性差异。
Dyslipidemia is common and frequently-occurring disorder. It is of importance nearly concerning coronary heart diseases, hypertension, type 2 diabetes, storke, etc. The prelance rate of dyslipidemia is greatly higher than before, and the mechanisms of dyslipidemia are being payed more attention to study. Now it is known that it is a disease caused by many factors such as diets, enviromenter, etc. Recently, it was reported that single nucleotide polymorphisms (SNPs) of some susceptibility gene were closely related with dyslipidemia as well. It is of great significance to study the susceptibility genes of dyslipidemia in order to prevent, delay or avoid the occurrence of this disease. Now it is known that dyslipidemia is relatied to many gene mutations, including genes of low density lipoprotein (LDL) receptor, lipoprotein, Angiotensin converting enzyme, cholesterol 7a-hydroxylase, proprotein convertase, analysin, cellular retinoic acid binding protein, cytochrome P4503A4, and 2C9, etc. Studies on the the relationship between dyslipidemia and those genes usually begin with detection of SNPs of these genes.
Human cytochrome P450 has series emzymes, taking important part in drug metabolism by human liver, and it also involves metabolism of many exogenous or endogenous substances. It is coded by CYP gene superfamily, consist of four families CYP 1-4, subfamilies of A, B, C, D, producing dozens of isozyme. CYP3A is the biggest family which contains four functional genes (CYP3A4, CYP3A5, CYP3A7 and CYP3A43) and two pseudogenes (CYP3AP1 and CYP3AP2). CYP3A5 is one of the subfamilies of CYP3A. CYP3A5 protein mainly distributes in the liver, also expressed in other organs such as kidney and lung. In some individuals CYP3A5 accounts for 50% of the total CYP3A in liver.
CYP3A5 protein is coded by CYP3A5 gene, located in q21-q22.1, with length of 31.0KB containing 3 exons. CYP3A5 gene has several sites with polymorphisms, wild type defined as* 1, and nearly 30 mutation types defined as CYP3A5*2,*3,*4、*5,*6,*7 and*8, etc. according to the time order of being found. It is already definite that the 6986 codon in the third intron of CYP3A5 gene is the key factor to determine the the expression and activity level of CYP3A5 protein. Mutation of CYP3A5 alleles distributes differently in different populations. In chanese people, the CYP3A5*3 gene type includes CYP3A5*1/*1 (AA, wild type), CYP3A5*1/*3 (GA, Heterozygous mutation), and CYP3A5*3/*3 (GG, Homozygous mutantion).
Polymorphisms of the CYP3A5 gene cause the changes of CYP3A5 protein structure, then the enzyme activity. It was reported that the activity of the mutation type is lower than the wild type, resulting in different catalytic abilities to metabolite exogenous and endogenous substances. People carrying the mutant gene have lower ability to metabolite some exogenous and endogenous substances than those carrying wild type gene, and then influence the occurrence and development of some diseases.
It is know that CYP3A5 involves transformation of many endogenous substances which are related with lipid metabolism and the polymorphisms of CYP3 A5 gene influence the hypolipidemic effect of statins. However the relationship of CYP3A5 itself and blood lipid level is still unknown. It was reported CYP3A4, 84%similar to CYP3A5 in structure and function, payed an important role in produce and elimination of cholesterol and hydroxycholesterol. Furthermore, CYP3A4 gene polymorphisms were found to be associated with blood lipid level. For example, patients with CYP3A4*3 have lower low density lipoprotein-cholesterol (LDL-C) in blood. On the otherhand, CYP3A5 involves hydroxyl reaction of 17-β-estradiol and estrone. It was reported that those estrogens can reduce low density lipoprotein-cholesterol (LDL-C) by increasing low density lipoprotein receptor (LDLR). So it was postulated that CYP3A5 gene polymorphisms might cause differences of hydroxyl reaction of estrogen in individuals, result in different level of estrogen in blood, and then the different risk of dyslipidemia. CYP2C9, another enzyme like CYP3A5 with ability to catalyze hydroxyl reaction of 17-(3-estradiol and estrone, was found to be related with dyslipidemia. Based on above research, we supposed that polymorphisms of CYP3A5 might be associated with blood lipid level.
Here, we carried out a case-control study using SNPs as a genetic marker detected by the real-time PCR with taqman MGB probe in order to investigate the relationship of CYP3A5*3 gene polymorphyrisms and dyslipidemia through correlation analysis. We want to explore the etiology and pathogenesis of this disease from the aspect of genetics and further provide the theory basis for prevention, individual prophylaxis and treatment of it.
Objective
1. To explore the relationship between the CYP3A5 gene polymorphylisms and dyslipidemia.
2. To investigate the relationship between the CYP3A5 gene polymorphylisms and the level of blood fat.
Subjects and methods
1. Subjects
All research objects were chosen from hospitalized patients in cardiovascular department or the healthy people for medical check-up in our hospital, including 321 patients with dyslipidemia and 258 healthy people. The diagnostic criteria of dyslipidemia includes two or more conditions below:total cholesterol (TC)≥5.72mmol/L, low density lipoprotein-cholesterol (LDL-C)> 3.36mmol/L, high density lipoprotein-cholesterol, (HDL-C)≤0.9 mmol/L, or triglyceride, (TG)≥1.70mmol/L, to fast twelve hour after detect. We recruited 162 males and 159 females with, dyslipidemia, the median age of 53.54±12.06. The standard of healthy control group include normal ranges of all blood lipid tests and normal blood routine, urine routine, blood coagulation, chest X-ray, blood biochemical test and ECG (electrocardiogram) as well. There are 111 males and 147 females recruited with the age of 52.69±11.66. All objects are natural, the Han people and unrelated, who don't have serious system diseases such as hepatopathy, nephropathy, tumor, diabetes, and don't to take medicine lipidemic modulating drugs in the near future, and women without the use of calcium and perimenopausal hormone replacement therapy.
2. Methods
Venous blood was taken from all objects after starving 12h. The plasma TC, LDL-C, HDL-C and TG were tested by standard enzyme colorimetric method. Another 5ml venous blood was taken into anticoagulation tube with EDTA-K2 to extract leukocyte genomic DNA according to the instruction of Human blood DNA extraction kit. Gene type of CYP3A5*3(6986A→G) was defined by real-time PCR with taqmanMGB probe. The blood fat level in people with wild type of CYP3A5*3 were compared with that in people with mutation type in dyslipidemia group and healthy group, respectively. Generl clinical characteristics such as age and sex were compared between two groups by independent-sample T test and one way ANOVA. Frequency of CYP3A5*3 gene type, allele frequency and blood fat level in two groups were compared by x2 test. P＜0.05 was considered to be significant.
Results
1. Dyslipidemia group and control group both have three gene types:AA wild type (CYP3A5*1/*1)、GA heterozygous mutation(CYP3A5*1/*3) and GG homozygous mutantion (CYP3A5*3/*3).
2. The frequncy of AA、GA、GG gene in dyslipidemia group are 9%,46.1% and 44.9%, compared with 9.7%,39.5%,50.8%in control group. A, G allele frequency are 32.1%and 67.9%in dyslipidemia group, compared with 29.5%and 70.5%in control group. There are no significant difference between two groups (P=0.279, P=0.336, respectively).
3. In dyslipidemia group and control group,though comparing the level of lipidemia in diffenent gene types high density lipoprotein-cholesterol (HDL-C) is significantly higher in patients with allele A (AA+GA) (1.30±0.33 mmol/L, 1.53±0.41 mmol/L) than those who carry GG homozygous((1.21±0.29 mmol/L, 1.42±0.36 mmol/L) (P=0.011,P=0.034, respectively). There were no significant difference in other lipid items between different gene type groups.
Conclusion
1. In han people, CYP3A5*3 allele gene includes three gene types:AA wild type (CYP3A5*1/*1), GA heterozygous mutation (CYP3A5*1/*3), and GG homozygous mutantion(CYP3A5*3/*3).
2. There are no significant differences in frequency of genotype and alleles of CYP3A5*3 between dyslipidemia group and control group, suggesting that dyslipidemia might not be related to CYP3A5*3 gene polymorphisms (P>0.05).
3. In dyslipidemia group and control group,though comparing the level of lipidemia in diffenent gene types high density lipoprotein-cholesterol (HDL-C) is significantly higher in patients with allele A (AA+GA) than those who carry GG homozygous (P<0.05).There were no significant difference in other lipid items between different gene type groups.
引文
[1]. Humphries SE, Cranston T, Allen M, et al. Mutation analysis in UK patients with a clinical diagnosis of fam ilial hypercholester-olaemia:relationship with plasma lipid traits, heart disease risk and utility in relative tracing[J]. Am J Med Genet, 2006,84:203-214.
[2]. Muallem H, North Ke, KakokiM, et al. Quantitative effects of common genetic variations in the 3URT of the human LDL-recep-tor gene and their associations with plasma lipid levels in the Ath-erosclerosis Risk in Communities study [J]. Hum Genet,2007,21:421-431
[3]. Rios DLS, Vargas AF, Torres MR, et al. Interaction between SREBP-la and APOB polymorphisms influences total and low-density lipoprotein cholesterol levels in patients with coronay artery disease[J]. Clin Genet,2003,63:380-385.
[4]. SNGCF, DAV IGNON K. Role of the Apolipoprotein E Polymorphism in Determining Normal Plasma Lipid and Lipoprotein Variation[J]. Am J Hum Genet,1985,37:268-285.
[5]. Clee SM, Zwinderman AH, Engert JC, et al. Common genetic variation in abcal is associated with altered lipoprotein levels and a modified risk for coronary artery disease[J]. Circulation,2001,103:1198-1205.
[6]. Eilertsen KE, lsen JO, Brox J et al. Association of the-159 ct polymorphism in the CD 14 promoter with variations in serum lipoproteins in healthy subjects[J]. Blood Coagul Fibrinolysis,2002,14:663-670.
[7]. Finta C, Zaphiropoulos PG. The human cytochrome P4503A locus Gene evolution by capture of downstream exons[J]. Gene.2000,260:13-23.
[8]. Jounaidi Y, Hyrailles V, Gervot L, et al. Detection of CYP3A5 allelic variant:a candidate for the polymorphic expression of the protein[J]. Biochem Biophys Res Commun,1996,221:466-470.
[9]. Busi F, Cresteil T. CYP3A5 mRNA degradation by nonsensc-mediated mRNA decay[J]. Mol Pharmacol.2005,68:808-815.
[10]. Shih PS, Huang JD. Pharmacokinetics of midazolam and l'-hydroxymidazolam in Chinese with different CYP3A5 genotypes. Drug Metabolism and Disposition,2002,30:1491-1496.
[11]. Li D, Zhang GL, Lou YQ, et al Genetic polymorphisms in MDR1 and CYP3A5 and MDR1 haplotype in mainland Chinese Han, Uygur and Kazakh ethnic groups. J Clin Pharm Ther,2007,32:89-95.
[12].Balram C, Zhou Q, Cheung YB, et al. CYP3A5*3 and*6 Single nucleotide polymorphisms in three distinct Asian populations[J]. European Journal of Clinical Pharmacology.2003,59:123-126
[13]. Kuehl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression[J]. Nat Genet.2001,27:383-391.
[14]. Langaee TY, Gong Y, Yarandi HN, et al. Association of CYP3A5 polymorphisms with hypertension and antihypertensive response to verapamil[J]. Clin Pharmacol Ther.2007,81:386-39.1.
[15]. Bjorkhem I, Diczfalusy U. Hydroxycholesterols-friends, foes or just fellow passangers. Arterioscler Thromb Vasc Biol.2002,22:734-742
[16]. Kajinami K, Brousseau ME, Ordovas JM,et al CYP3A4 genotypes and plasma lipoprotein levels before and after treatment with atorvastatin in primary hypercholesterolemia[J]. Am J Cardiol,2004,93:104-107.
[17]. Lee AJ, Cai MX, Thomas PE,et al. Characterization of the oxidative metabolites of 17beta-estradiol and estrone formed by 15 selectively expressed human cytochrome p450 isoforms[J]. Endocrinology,2003,144:3382-3398.
[18]. Petitti DB, Perlman JA, Sidney S. Noncontraceptive estrogens and mortality: long-tem follow of women in the Walnut Greek Study. Obster Gynecol,1987, 70:289-293.
[19]. Kirk EA, Sutherland P, Wang SA, et al. Dietary isoflavones reduce plasma cholesterol and atherosclerosis in C57BL/6 mice but not LDL receptor deficient mice[J]. J Nutr,1998,128:954-959.
[20]. Luo CH, Wang A, Zhu RH, et al Gender specific association of CYP2C9*3 with hyperlipidaemia in Chinese[J]. Br J Clin Pharmacol,2005,60:629-631.
[21]. Yong-Fang Hu, Jun He, Guo-Lin Chen, et al CYP3A5*3 and CYP3A4*18 single nucleotide polymorphisms in a Chinese population[J]. Clinica Chimica Acta,2005,353:187-192.
[22]. Fukuen S, Fukuda T, Maune H, et al. Novel detection assay by PCR-RFLP and frequency of the CYP3A5 SNPs, CYP3A5*3 and*6, in a Japanese popu-lation[J]. Pharmacogenetics,2002,12:331-334.
[23].韦侃侃,贾敏,付强等.影响他汀类药物降脂治疗的相关基因的多态性及与高脂血症的关系[J].中国新药与临床杂志,2008,27：570-575.
[24]. Luoma PV, Pelkonen RO, Sotaniemi EA. Plasma highdensity lipoprotein cholesterol and hepatic drug metabolizing enzyme activity in man[J]. Acta Physiol Scand Suppl,1979,473:71
[25]. Bjorkhem I, Diczfalusy U, Lutjohann D.Removal of cholesterol from extrahepatic sources by oxidative mechanisms[J]. Curr Opin Lipidol,1999, 10:161-165.
[26]. Tontonoz P, Mangelsdorf DJ. Liver X receptor signaling pathways in car-diovascular disease[J]. Mol Endocrinol,2003,17:985-993.
[27]. Pauli V. Luoma. Cytochrome P450 and gene activation-from pharmacology to cholesterol elimination and regression of atherosclerosis. Eur J Clin Pharmacol. 2008,64:841-850.
[28]. Ory DS. Nuclear receptor signaling in the control of cholesterol homeostasis: have the orphans found a home[J]. Circ Res,2004,95:660-670.
[29]. Williams JA, Ring BJ, Cantrell VE, et al. Comparative metabolic capabilities of CYP3A4, CYP3A5, and CYP3A7[J]. Drug Metab Dispos,2002, 30:883-891.
[1]. Burk O, Koch I, Raucy J, et al. The induction of cytochrome P450 3A5 CYP3A5) in the human liver and intestine is mediated by the xenobiotic sensors pregnane X receptor PXR) and constitutively activated receptor CAR) [J]. J Biol Chem.2004,279(37):38379-38385.
[2]. Wrighton SA, Brian WR, Sari MA, et al. Studies on the expression and metabolic capabilities of human liver cytochrome P450IIIA5(HLp3) [J]. Mol Pharmacol.1990,38(2):207-213.
[3]. Kuehl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression[J]. Nat Genet.2001,27(4):383-391.
[4].Chowbay B, Zhou S, Lee EJ. An interethnic comparison of polymorphisms of the genes encoding drug-metabolizing enzymes and drug transporters: experience in Singapore[J]. Drug Metab Rev.2005,37(2):327-378.
[5]. Jounaidi Y, Hyrailles V, Gervot L, et al. Detection of CYP3A5 allelic variant:a candidate for the polymorphic expression of the protein[J]. Biochem Biophys Res Commun.1996,221(2):466-470.
[6].Busi F, Cresteil T. CYP3A5 mRNA degradation by nonsense-mediated mRNA decay[J]. Mol Pharmacol.2005,68(3):808-815.
[7].Langaee TY, Gong Y, Yarandi HN, et al. Association of CYP3A5 polymorphisms with hypertension and antihypertensive response to verapamil[J]. Clin Pharmacol Ther.2007,81(3):386-391.
[8].Shih PS, Huang JD. Pharmacokinetics of midazolam and l'-hydroxymidazolam in Chinese with different CYP3A5 genotypes[J]. Drug Metabolism and Disposition.2002,30(12):1491-1496.
[9].Li D, Zhang GL, Lou YQ, et al. Genetic polymorphisms in MDR1 and CYP3A5 and MDR1 haplotype in mainland Chinese Han, Uygur and Kazakh ethnic groups[J]. J Clin Pharm Ther.2007,32(1):89-95.
[10].Balram C, Zhou Q, Cheung YB, et al. CYP3A5*3 and*6 Single nucleotide polymorphisms in three distinct Asian populations[J]. European Journal of Clinical Pharmacology.2003,59(2):123-126.
[11].Hustert E, Haberl M, Burk O, et al. The genetic determinants of the CYP3A5 polymorphism[J]. Pharmacogenetics.2001,11(9):773-779.
[12].Paulussen A, Lavrijsen K, Bohets H et al. Two linked mutations in transcriptional regulatory elements of the CYP3A5 gene constitute the major genetic determination of polymorphic activity in humans[J]. Pharmacogenetics.2000,10(5):415-424.
[13].Wong M, Balleine RL, Collins M, et al. CYP3A5 genotype and midazolam clearance in Australian patients receiving chemotherapy[J]. Clin. Pharmacol. Ther.2004,75(6):529-538.
[14].胡永芳,翟所迪,邱雯等.CYP3A5*3和CYP3A4*18B基因多态性对肾移植患者环孢素药代动力学的影响[J].中国药理学通报.2009,25(3)：378-382.
[15].陈劲松,黎磊石,唐政等.CYP3A5基因型对肾移植术后他克莫司血药浓度及疗效的影响[J].肾脏病与透析肾移植杂志.2008,17(1)：4-8.
[16].Liu TC, Lin SF, Chen TP, et al. Polymorphism analysis of CYP3A5 in myeloid leukemia[J]. Oncol Rep.2002,9(2):327-329.
[17].Pakakasama S, Mukda E, Sasanakul W, et al. Polymorphisms of drug metabolizing enzymes and risk of childhood acute lymphoblastic leukemia[J]. Am J Hematol.2005,79(3):202-205.
[18].Wang T, Chen FY, Han JY, et al. The relationship between cytochrome P450, subfamily IIIA, polypeptide 5 gene and drug resistance in leukemia cell lines[J]. Zhonghua Nei Ke Za Zhi.2004,43(7):527-529.
[19].Shen LJ, Chen FY, Wang T, et al. Polymorphisms of CYP3A5 gene in acute leukemia patients and their role in chemotherapy and prognosis[J]. Zhongguo Shi Yan Xue Ye Xue Za Zhi.2008,16(1):26-30.
[20].Huang Z, Chai YH, Cen JN.et al. Expression of CYP3A5 mRNA in children with acute leukemia[J]. Zhongguo Dang Dai Er Ke Za Zhi. 2009,11(7):549-554.
[21].Hiratsuka M, Takekuma Y, Endo N, et al. Allele and genotype frequencies of CYP2B6 and CYP3A5 in the Janpanese population[J]. Eur J Clin Pharmacol. 2002,58(6):417-421.
[22].S Leskela1, E Honrado2, C Montero-Conde2, et al. Cytochrome P4503A5 is highly expressed in normal prostate cells but absent in prostate cancer[J]. Endocrine-Related Cancer.2007,14(3):645-654.
[23].李振华,孔垂泽,王立忠.前列腺癌发生风险与CYP3A5基因多态性的关系[J].中华实验外科杂志.2003,12(20)：1098-1099.
[24].Yeh KT, Chen JC, Chen CM, et al. CYP3A5*1 is an inhibitory factor for lung cancer in Taiwanese[J]. Kaohsiung J Med Sci.2003,19(5):201-207.
[25].Sampsonas F, Karkoulias K, Kaparianos A, et al. Genetics of chronic obstructive pulmonary disease, beyond al-antitrypsin deficiency [J]. Curr Med Chem.2006,13(24):2857-2873.
[26].Zhang JY, Wang Y, Prakash C. Xenobiotic-metabolizing enzymes in human lung[J]. Curr Drug Metab.2006,7(8):939-948.
[27].Raunio H, Hakkola J, Pelkonen O. Regulation of CYP3A genes in the human respiratory tract[J]. Chem Biol Interact.2005,151(2):53-62.
[28].Takayuki Seoa, Punam Pahwab, Helen H, et al. Association between cytochrome P4503A5 polymorphism and the lung function in Saskatchewan grain workers[J]. Pharmacogenetics and Genomics.2008,18(6):487-493.
[29].Givens RC, Lin YS, Dowling AL, et al. CYP3A5 genotype predicts renal CYP3A activity and blood pressure in healthy adults[J]. J Appl Physiol.2003, 95(3):1297-1300.
[30].Blaustein MP, Grim CE. The pathogenesis of hypertension:black-white differences[J]. Cardiovasc Clin.1991,21(3):97-114.
[31].Herbert HO, Amar Pinto, Stephen D, et al. Association Between the CYP3A5 Genotype and Blood Pressure[J]. Hypertension.2005, 45(2):294-298.
[32].Kivisto KT, Niemi M, Schaeffeler E, et al. CYP3A5 genotype is associated with diagnosis of hypertension in elderly patients:data from the DEBATE study[J]. Am J Pharmacogenom.2005,5(3):191-195.
[33].Martin F. Fromma, Bernhard M.W. Schmidt, Andreas Pahl, et al. CYP3A5 genotype is associated with elevated blood pressure[J]. Pharmacogenetics and Genomics.2005,15(10):737-741.
[34].Murray Gl, McFadyen MC, Mitchell RT, et al. Cytochrome P450 CYP3A in human renal cell cancer[J]. Br J Cancer.1999,79(11-12):1836-1842.
[35].Ghosh SS, Basu AK, Ghosh S, et al. Renal and hepatic family 3A cytochromes P450(CYP3A) in spontaneously hypertensive rats[J]. Biochem Pharmacol.1995,50(1):49-54.
[36].Daly AK. Significance of the minor cytochrome P450 3A isoforms[J].Clin Pharm acokinet.2006,45(1):13-31.
[37].Canonico M, Bouaziz E, Carcaillon L, et al. Synergism between oral estrogen therapy and cytochrome P4503A5*1 allele on the risk of venous thromboembolism among postmenopausal women[J]. J Clin Endocrinol Metab. 2008,93(8):3082-7. Epub 2008 Jul 15.